FI86413C - FOERFARANDE FOER FRAMSTAELLNING AV 2,4-DICHLORO-5-FLUORBENOESYRA. - Google Patents

Description

1 86413

Process for the preparation of 2,4-dichloro-5-fluoro-benzoic acid

The present invention relates to a new process for the preparation of an intermediate for the preparation of anti-5 bacterial agents, 2,4-dichloro-5-fluorobenzoic acid.

It is known that trihalobenzoic acids can be prepared by saponifying trihalogen-trihalogen-10 methylbenzene. In this case, 2,4-dichloro-5-fluoro-trichloromethylbenzene is formed by saponification of 2,4-dichloro-5-fluorobenzoic acid (EP-OS 78 362).

In addition, it is known that acylation with aliphatic carboxylic acid halides is very difficult in the case of dihalobenzenes and no acylation occurs at all in the case of trihalobenzenes (see Methoden der organischen Chemie (Houben-Weyl-Muller) 1973, Vol. 7 / 2a, 43). , Thieme-Verlag, Stuttgart).

It is also known that acylation with carboxylic acid anhydrides, such as acetic anhydride, gives 2,4-dichlorofluorobenzene in the presence of aluminum trichloride in poor yield of 2,4-dichloro-5-fluoroacetophenone (see CA 58, 11243 g).

It has now surprisingly been found that 2,4-dichloro-5-fluorobenzoic acid of the formula (I) _ / C130 Cl- ^ y-cooH (i) is obtained in good yield and in very pure reaction. 2,4-dichlorofluorobenzene with acetyl chloride in the presence of acylation catalysts and possibly in the presence of 2,86413 diluents, at temperatures between 10 and 150 ° C, and the reaction product thus reacted with 2,4-dichloro-5-fluoro acetophenone of formula (II). .....

10 optionally after isolation with sodium hypochlorite solution (in the form of so-called chlorine liquor) at a temperature between 0-140 ° C.

Surprisingly, process 15 according to the invention makes it possible to carry out the acylation of 2,4-dichlorofluorobenzene with carboxylic acid chloride in the meta position with respect to the more electronegative halogen in high yield and selectivity. This is all the more surprising since, according to the prior art, in the acylation of halobenzenes, it would have been expected that the acylation would have taken place in the ortho or para position with respect to the more electronegative halogen (see "Methoden der organischen. Chemie" (Houben-Weyl-Miiller), bond 7 / 2a 43 (1973), Thieme- · Verlag, Stuttgart).

'·' · 25 The above-mentioned known methods have a number of drawbacks. Thus, in the preparation of 2,4-dichloro-5-fluoro-trichloromethylbenzene, the intermediate is formed - * - | triazene, which is difficult to handle due to its unfavorable physiological properties.

In addition, this method requires 2,4-di-. . : several steps for the preparation of chloro-5-fluoro-benzoic acid.

In the acylation of 2,4-dichloro-5-fluorobenzene 35 described in the literature in the presence of acetic anhydride: the yield of the reaction product is rather low.

li 3 86413

If 2,4-dichlorofluorobenzene and acetyl chloride, aluminum chloride as catalyst and chlorine liquor are used as starting materials, the reaction procedure can be shown by the following reaction scheme: 5 C1r- £ f * »3-co-ci 10 __

Chlorine liquor v / TT \

- * CJv_y-cooH

2,4-Dichlorofluorobenzene is a known compound of organic chemistry.

The reaction temperature can be varied over a relatively wide range. Thus, the acylation is generally carried out at temperatures between 10 and 150 ° C, preferably between 20 and 130 ° C, in particular between 80 and 130 ° C. Subsequent oxidation with so-called chlorine liquor is generally carried out at temperatures between 0 and 140 ° C, preferably between 20 and 120 ° C. The reaction is usually carried out at atmospheric pressure.

The process according to the invention is preferably carried out without diluents.

Suitable catalysts for the process according to the invention are acylation catalysts, such as, for example, ferric chloride, zinc chloride or aluminum chloride, preferably aluminum chloride.

; Suitable oxidizing agents for the process according to the invention are the so-called chlorine lye, an aqueous solution of sodium hypochlorite.

In carrying out the process according to the invention, 1 to 3 moles of acetyl chloride and 1 to 3 moles of aluminum chloride are generally used per mole of 2,4-dichlorofluorobenzene. After completion of the reaction, the reaction mixture is poured onto ice and taken up in a water-immiscible diluent such as, for example, methylene chloride or chloroform. The reaction-5 product can also be isolated without the use of diluents. Optionally, after removal of the extractant, the residue is oxidized in the presence of 2 to 4 liters, preferably 2.1 to 3.3 liters of chlorine solution (150 g of active chlorine / l) per mole of starting material. The 2,4-di-10-chloro-5-fluorobenzoic acid is then precipitated with a mineral acid such as hydrochloric acid and then filtered through a suction filter.

According to the process of the invention, readily available 2,4-dichloro-5-fluorobenzoic acid can be used, for example, for the synthesis of antibacterial agents. Thus, 15-oxyquinolinecarboxylic acids, compounds with high bactericidal activity can be prepared from this acid according to the following equations (see, e.g., EP-OS 78 362): I: 5 86413

Cl - ^ ^ COOH ioci2_> C] ^ COCl CH2 (COOC? H <)? 5 cj CD0C2h5) 2 -> C1 - ^ _ \ ^ C0-CH2-CO 0C2H5 0C2H 5 10 hc (oc2h5) 3—> cl ^ yco - ^ - CoOC2H5 -? -> ”N <] 0 _ Cl CH Fv ^ sV ^ \ ^, (: 0DC2H5 15 Cl V / NY C0-t? -CD0C2H5 -> jL '[I -> Ä 0 / - \ 0

20 F ^ v ^ A ^ COOH RNI NH CDOH

- c £ 0 w

1 RN N J

Δ w Δ 25 R = H, alkyl • »I • · · • · · · · · · · Preparation example • · · ·" "....... 1 • · ♦ 30 _Cl

...: Cl _ \\ - COOH

λ / (I): V To a mixture of 33 g (0.2 moles) of dichlorofluorobenzene and 66.8 g (0.5 moles) of aluminum m • · · • · · • · · · • · · 6 86413 chloride, 23.6 g (0.3 mol) of acetyl chloride are added at 20-40 ° C and then stirred for 2 hours at 120 ° C. The still hot mixture is poured onto 250 g of ice and the oil which separates is taken up in methylene chloride. The solvent is evaporated off and 450 ml of chlorine solution (150 g of active chlorine / l) are added to the residue and the mixture is stirred for one hour without heating and then for 2 hours by refluxing. After separation of the chloroform formed, 300 ml of water are added, followed by 10 ml of a 40% solution of sodium hydrogen sulphite and then concentrated hydrochloric acid until pH 1 is reached.

In this way, 33.5 g (80% of theory) of 2,4-dichloro-5-fluorobenzoic acid are obtained in the form of a colorless powder with a melting point of 139 ° C.

Claims (5)

A process for the preparation of 2,4-dichloro-5-fluoro-benzoic acid of formula (I) F characterized in that the 2,4-dichlorofluorobenzene is reacted with acetyl chloride in the presence of acylation catalysts and optionally in the presence of diluent at temperatures between 10 ° C and 150 ° C, and the thus obtained the reaction product 2,4-dichloro-5-fluoroacetophenone of formula (II) 20 / -C C 1 C 1 The reaction mixture is reacted, optionally after isolation, with sodium hypochlorite solution (in the form of the so-called chlorine liquor) at a temperature 1 between 0 ° C and 140 ° C and the compound of formula (I) is isolated according to conventional methods. 2. A process according to claim 1, characterized in that, as an acylation catalyst, aluminum trichloride is used. 3. A process according to claims 1 and 2, characterized in that the reaction with acetyl chloride is carried out at temperatures between 20 ° C and 130 ° C. 4. Process according to claims 1 and 2, characterized in that the reaction with the sodium hypochlorite solution (chlorine liquor) is carried out at temperatures between 20 ° C and 120 ° C. 5. A process according to claims 1-4, characterized in that the 2,4-dichloro-5-fluoroacetophenone obtained during the process 5 is reacted without isolation with the sodium hypochlorite solution (chlorine liquor). li